| Structural highlights
Function
TERF2_HUMAN Binds the telomeric double-stranded 5'-TTAGGG-3' repeat and plays a central role in telomere maintenance and protection against end-to-end fusion of chromosomes. In addition to its telomeric DNA-binding role, required to recruit a number of factors and enzymes required for telomere protection, including the shelterin complex, TERF2IP/RAP1 and DCLRE1B/Apollo. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded 5'-TTAGGG-3' repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Together with DCLRE1B/Apollo, plays a key role in telomeric loop (T loop) formation by generating 3' single-stranded overhang at the leading end telomeres: T loops have been proposed to protect chromosome ends from degradation and repair. Required both to recruit DCLRE1B/Apollo to telomeres and activate the exonuclease activity of DCLRE1B/Apollo. Preferentially binds to positive supercoiled DNA. Together with DCLRE1B/Apollo, required to control the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Recruits TERF2IP/RAP1 to telomeres, thereby participating in to repressing homology-directed repair (HDR), which can affect telomere length.[1] [2] [3]
Publication Abstract from PubMed
Telomeric repeat binding factor 2 (TRF2) is a telomere-associated protein that plays an important role in the formation of the 3' single strand DNA overhang and the "T loop", two structures critical for the stability of the telomeres. Apollo is a 5'-exonuclease recruited by TRF2 to the telomere and contributes to the formation of the 3' single strand DNA overhang. Knocking down of Apollo can induce DNA damage response similar to that caused by the knocking down of TRF2. In this Letter, we report the design and synthesis of a class of cyclic peptidic mimetics of the TRFH binding motif of Apollo (ApolloTBM). We found conformational control of the C terminal residues of ApolloTBM can effectively improve the binding affinity. We have obtained a crystal structure of a cyclic peptidic Apollo peptide mimetic (34) complexed with TRF2, which provides valuable guidance to the future design of TRF2 inhibitors.
Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction.,Chen X, Liu L, Chen Y, Yang Y, Yang CY, Guo T, Lei M, Sun H, Wang S ACS Med Chem Lett. 2018 Apr 25;9(5):507-511. doi: 10.1021/acsmedchemlett.8b00152., eCollection 2018 May 10. PMID:29795768[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998 Feb 6;92(3):401-13. PMID:9476899
- ↑ de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005 Sep 15;19(18):2100-10. PMID:16166375 doi:10.1101/gad.1346005
- ↑ Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A, Benarroch D, Magdinier F, Morere J, Amiard S, Verhoeyen E, Britton S, Calsou P, Salles B, Bizard A, Nadal M, Salvati E, Sabatier L, Wu Y, Biroccio A, Londono-Vallejo A, Giraud-Panis MJ, Gilson E. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010 Jul 23;142(2):230-42. doi: 10.1016/j.cell.2010.05.032. PMID:20655466 doi:10.1016/j.cell.2010.05.032
- ↑ Chen X, Liu L, Chen Y, Yang Y, Yang CY, Guo T, Lei M, Sun H, Wang S. Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction. ACS Med Chem Lett. 2018 Apr 25;9(5):507-511. doi: 10.1021/acsmedchemlett.8b00152., eCollection 2018 May 10. PMID:29795768 doi:http://dx.doi.org/10.1021/acsmedchemlett.8b00152
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